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Molecular Mediator of Prostate Cancer Progression and Its Implication in Therapy
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Samikshan Dutta, Navatha Shree Sharma, Ridwan Islam, Kaustubh Datta
TCGA database suggested mutations in many DNA repair genes like BRCA1, BRCA2, FANCD2, CKD12 and ATM in primary prostate cancer, although it is to be noted that the frequency of DNA repair mutations in localized prostate cancer is low [108, 178, 179]. Interestingly, mutations in DNA repair enzymes (BRCA2, ATM, BRCA1, FANCA, RAD51B, RAD51C, MLH1, and MSH2) are the major disease-specific mutations in mCRPC [180, 181]. The understanding that a quarter of men with mCRPC have mutations in DNA repair pathway genes such as BRCA genes has led to clinical trials with poly ADP ribose polymerase (PARP) inhibitors. PARPs are required to repair the DNA single-strand breaks through base-excision repair. It has been shown that cancer cells with BRCA gene mutations become significantly more sensitive to PARP inhibitors as a therapeutic approach popularly known as synthetic lethal strategy [180, 181]. It is further noted that mutations of other DNA repair pathway genes can be sensitive to PARP inhibitors. These genes are ATM, BRIP1, BARD1, CDK12, CHEK2, FANCA, NBN, PALB2, and RAD51 [182, 183].
Precision medicine in ovarian carcinoma
Published in Debmalya Barh, Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Shailendra Dwivedi, Purvi Purohit, Radhieka Misra, Jeewan Ram Vishnoi, Apul Goel, Puneet Pareek, Sanjay Khattri, Praveen Sharma, Sanjeev Misra, Kamlesh Kumar Pant
Bell et al. (2011) completed a study based on 316 HGS-OvCa samples and compared with normal samples for each individual. The study was based on captured 180,000 exons from 18,500 genes totaling 33 megabases of nonredundant sequence. Enormously parallel sequencing by using the Illumina GAIIx platform or ABI SOLiD 3 platform (80 sample pairs) obtained 14 gigabases per sample bases in total. TP53 was mutated in 303 of 316 samples. BRCA1 and BRCA2 had germ-line mutations in 9% and 8% of cases, respectively, and showed somatic mutations in a further 3% of cases. Further, this group also demonstrated the presence of other mutated genes: RB1, NF1, FAT3, CSMD3, GABRA6, and CDK12.
A patent and literature review of CDK12 inhibitors
Published in Expert Opinion on Therapeutic Patents, 2022
Ruijun Tang, Jing Liu, Shuyao Li, Junjie Zhang, Chunhong Yu, Honglu Liu, Fang Chen, Lu Lv, Qian Zhang, Kai Yuan, Hao Shao
CDK12 emerges as both tumor suppressor and oncogene. CDK12 mutations were identified in breast [11], ovarian [12] and prostate [13] cancers, indicating its role as a tumor suppressor. CDK12 mutations define an aggressive subgroup with poor prognosis in prostate cancer [14], and clinical trials using CDK12 as a biomarker have been initiated. In addition to its potential role as a biomarker, recent studies have highlighted CDK12 as a promising therapeutic target for cancer [15–20]. In breast cancers, CDK12 is frequently co-amplified with HER2, and CDK12-mediated overexpression of several WNT ligands and components of the ERBB–PI3K (phosphatidylinositol-3-kinase)–AKT pathway contributes to the resistance of anti-HER2 monoclonal antibody trastuzumab [10,21]. Several studies have identified that inhibition of CDK12 is synthetic lethal with cMYC [22] and EWS/FLI fusion protein over-expressing cancers [23]. Since CDK12 is associated with the expression of DDR genes, its inhibition sensitized cancer cells to PARP (poly ADP-ribose polymerase), DNA-damaging agents, and CHK1 inhibitors [24–26].
Aberrations of DNA repair pathways in prostate cancer: a cornerstone of precision oncology
Published in Expert Opinion on Therapeutic Targets, 2021
Stergios Boussios, Elie Rassy, Sidrah Shah, Evangelia Ioannidou, Matin Sheriff, Nicholas Pavlidis
MMR deficiency leads to the accumulation of somatic mutations that generate neoantigens. The correlation of neoantigens with cancer immunity provides the therapeutic rationale of immune checkpoint inhibitors in this subset of MMR-deficient tumors. CDK12 has a role in controlling genomic stability through regulation of DDR genes. Translational studies have shown that CDK12 mutations may delineate an immuno-responsive subgroup of prostate cancer, characterized by increased levels of T cell infiltration and high neoantigen burden. In this regard, anti-programmed cell death 1 (PD1) monotherapy may also be effective. However, exploratory analysis of data from the phase 2 KEYNOTE-199 trial of pembrolizumab in mCRPC patients did not correlate potential efficacy of pembrolizumab with DDR defects or MMR deficiency [14]. A combined treatment with CDK12 and immune checkpoint inhibitors for prostate cancer may be suggested by the immune phenotype of CDK12-mutated tumors.
Cyclin-dependent kinase inhibition and its intersection with immunotherapy in breast cancer: more than CDK4/6 inhibition
Published in Expert Opinion on Investigational Drugs, 2022
Xianan Guo, Huihui Chen, Yunxiang Zhou, Lu Shen, Shijie Wu, Yiding Chen
CDK12 is a transcription-associated CDK that affects multiple cellular processes including transcription, RNA splicing, DNA damage response (DDR), and maintenance of genomic stability. There are three cyclins, cyclin L1, cyclin L2, and cyclin K, that are proven to interface with CDK12 [44–46].